Abstract:

A process is provided for efficiently producing an optically active
3-quinuclidinol derivative of high optical purity using a readily
available ruthenium compound as an asymmetric reduction catalyst. This
process is a process for producing an optically active 3-quinuclidinol
derivative represented by the following formula (III) comprising
asymmetrically hydrogenating a 3-quinuclidinone derivative represented by
the following formula (I) in the presence of a ruthenium compound (II)
represented by formula (II):
Ru(X)(Y)(Px)n[R1R2C*(NR3R4)-A-R5R6C*(N-
R7R8)] (in the formulas, R represents a hydrogen atom or C7 to
C18 aralkyl group and the like, X and Y represent hydrogen atoms or
halogen atoms and the like, Px represents a phosphine ligand, n
represents 1 or 2, R1 to R8 represent hydrogen atoms or C1 to C20 alkyl
groups and the like, * represents an optically active carbon atom and A
represents an ethylene group and the like).
##STR00001##

Claims:

1. A process for producing an optically active 3-quinuclidinol derivative
represented by formula (III): ##STR00014## (wherein, R represents a
hydrogen atom, an unsubstituted or substituted C1 to C20 alkyl group, an
unsubstituted or substituted C2 to C20 alkenyl group, an unsubstituted or
substituted C3 to C8 cycloalkyl group, an unsubstituted or substituted C5
to C6 cycloalkenyl group, an unsubstituted or substituted C7 to C18
aralkyl group or an unsubstituted or substituted C6 to C18 aryl group,
and * represents an optically active carbon atom), comprising:
asymmetrically hydrogenating a 3-quinuclidinone derivative represented by
formula (I): ##STR00015## (wherein, R is the same as previously defined)
in the presence of a ruthenium compound represented by formula
(II):Ru(X)(Y)(Px)n[R1R2C*(NR3R4)-A-R5R6C*(NR7R8)] (II)(wherein,X and Y respectively and independently
represent a hydrogen atom, a halogen atom, a carboxylate, a hydroxyl
group or a C1 to C20 alkoxy group;Px represents a phosphine ligand;n
represents 1 or 2;R1 to R8 respectively and independently
represent a hydrogen atom, an unsubstituted or substituted C1 to C20
alkyl group, an unsubstituted or substituted C2 to C20 alkenyl group, an
unsubstituted or substituted C3 to C8 cycloalkyl group, an unsubstituted
or substituted C5 to C6 cycloalkenyl group, an unsubstituted or
substituted C7 to C18 aralkyl group or an unsubstituted or substituted C6
to C18 aryl group, or either of R1 and R2 may bond with either
of R3 and R4, and either of R5 and R6 may bond with
either of R7 and R8, to form a ring;* is the same as previously
defined; and,A represents an unsubstituted or substituted C1 to C3
alkylene group that may have ether bond(s), an unsubstituted or
substituted C3 to C8 cycloalkylene group, an unsubstituted or substituted
arylene group or an unsubstituted or substituted divalent heterocyclic
group, and in the case A is an unsubstituted or substituted C1 to C3
alkylene group, either of R1 and R2 and either of R5 and
R6 may bond to form a ring).

2. A process for producing an optically active 3-quinuclidinol derivative
represented by formula (III-1): ##STR00016## (wherein, R represents a
hydrogen atom, an unsubstituted or substituted C1 to C20 alkyl group, an
unsubstituted or substituted C2 to C20 alkenyl group, an unsubstituted or
substituted C3 to C8 cycloalkyl group, an unsubstituted or substituted C5
to C6 cycloalkenyl group, an unsubstituted or substituted C7 to C18
aralkyl group or an unsubstituted or substituted C6 to C18 aryl group,
and * represents an optically active carbon atom, and ** represents an
optically active carbon atom in the case R is other than a hydrogen
atom), comprising: asymmetrically dehydrogenating a 3-quinuclidinone
derivative represented by formula (I-1): ##STR00017## (wherein, R is the
same as previously defined) in the presence of a ruthenium compound
represented by the formula (II).

3. The process for producing an optically active 3-quinuclidinol
derivative according to claim 1, wherein the ruthenium compound
represented by formula (II) is a ruthenium compound represented by
formula (II-1):Ru(X)(Y)(Px)n[R1C*H(NR3R4)-A-R1C*-
H(NR3R4)] (II-1)(wherein, X, Y, Px, n, R1, R3,
R4, * and A are the same as previously defined).

4. The process for producing an optically active 3-quinuclidinol
derivative according to claim 1, wherein the ruthenium compound
represented by formula (II) is a ruthenium compound represented by
formula (II-2):Ru(X)(Y)(Px)n[R1C*H(NH2)-A-R1C*H(NH.su-
b.2)] (II-2)(wherein, X, Y, Px, n, R1, * and A are the same as
previously defined).

5. The process for producing an optically active 3-quinuclidinol
derivative according to claim 1, wherein the ruthenium compound
represented by formula (II) is a ruthenium compound represented by
formula (II-3):Ru(X)2(Pxx)[R1C*H(NH2)-A-R1C*H(NH2)] (II-3)(wherein, X, R1, * and A are the same as previously
defined, and Pxx represents an optically active phosphine ligand).

6. The process for producing an optically active 3-quinuclidinol
derivative according to claim 2, wherein the ruthenium compound
represented by formula (II) is a ruthenium compound represented by
formula (II-1):Ru(X)(Y)(Px)n[R1C*H(NR3R4)-A-R1C*-
H(NR3R4)] (II-1)(wherein, X, Y, Px, n, R1, R3,
R4, * and A are the same as previously defined).

7. The process for producing an optically active 3-quinuclidinol
derivative according to claim 2, wherein the ruthenium compound
represented by formula (II) is a ruthenium compound represented by
formula (II-2):Ru(X)(Y)(Px)n[R1C*H(NH2)-A-R1C*H(NH.su-
b.2)] (II-2)(wherein, X, Y, Px, n, R1, and A are the same as
previously defined).

8. The process for producing an optically active 3-quinuclidinol
derivative according to claim 2, wherein the ruthenium compound
represented by formula (II) is a ruthenium compound represented by
formula (II-3):Ru(X)2(Pxx)[R1C*H(NH2)-A-R1C*H(NH2)] (II-3)(wherein, X, R1, * and A are the same as previously
defined, and Pxx represents an optically active phosphine ligand).

Description:

TECHNICAL FIELD

[0001]The present invention relates to a process for producing optically
active 3-quinuclidinol derivatives that are useful as production raw
materials of physiologically active substances, and particularly
pharmaceuticals.

[0002]The present application claims priority on Japanese Patent
Application No. 2007-230973, filed on Sep. 6, 2007, and Japanese Patent
Application No. 2008-032311, filed on Feb. 13, 2008, the contents of
which are incorporated herein by reference.

BACKGROUND OF THE ART

[0003]Many alkaloids, and particularly those compounds having an
azabicyclo ring structure, are useful as physiologically active
substances. In particular, optically active 3-quinuclidinol derivatives
are important compounds as production raw materials of pharmaceuticals.

[0004]A conventionally known process for industrial production of
optically active 3-quinuclidinol consists of direct asymmetric
hydrogenation of 3-quinuclidinone using inexpensive hydrogen gas for the
hydrogen source in the presence of an asymmetric hydrogenation catalyst
(Patent Documents 1 to 4).

[0005]In this production process, an optically active transition metal
complex having an optically active diphosphine and 1,2-diamine as ligands
is used for the asymmetric hydrogenation catalyst.

[0006]For example, the optically active transition metal complex described
in Patent Document 1 has a bisbinaphthyl compound derivative having an
asymmetric axis for the optically active diphosphine ligand, that
described in Patent Document 2 has a bisbiphenyl compound derivative
having an asymmetric axis for the optically active diphosphine ligand,
that described in Patent Document 3 has a ferrocene compound derivative
having an optically active group in a side chain thereof for the
optically active diphosphine ligand, and that described in Patent
Document 4 has an alkane compound derivative having an asymmetric carbon
for the optically active diphosphine ligand. In addition, the optically
active transition metal complexes of all of these patent, documents have
optically active or racemic 1,2-diamine compounds as diamine ligands.
Hydrogenation reactions are allowed to proceed under mild conditions by
all of the asymmetric hydrogenation catalysts described in these
publications.

[0007]However, the processes described in Patent Documents 1 and 3 have
low enantiomeric excess for the resulting quinuclidinol and low catalyst
efficiency, the process described in Patent Document 2 has low catalyst
efficiency, and the process described in Patent Document 4 has low
enantiomeric excess for the resulting quinuclidinol.

[0008]Thus, there is a desire for the development of a process that
enables direct asymmetric hydrogenation of 3-quinuclidinone having high
attainment rates for both enantiomeric excess and catalyst efficiency.
[0009][Patent Document 1] Japanese Unexamined Patent Application, First
Publication No. 2003-277380 [0010][Patent Document 2] Japanese Unexamined
Patent Application, First Publication No. 2005-306804 [0011][Patent
Document 3] Japanese Unexamined Patent Application, First Publication No.
2004-292434 [0012][Patent Document 4] International Publication No. WO
2006-103756

DISCLOSURE OF THE INVENTION

Problems to be Solved by the Invention

[0013]With the foregoing in view, an object of the present invention is to
provide a process for efficiently producing 3-quinuclidinol derivatives
of high optical purity by direct asymmetric hydrogenation of
3-quinuclidinone derivatives at high attainment rates for both
enantiomeric excess (or enantiomeric excess and diastereomeric excess)
and catalyst efficiency.

Means for Solving the Problems

[0014]In order to solve the aforementioned problems, the inventors of the
present invention conducted extensive studies on processes for direct
asymmetric hydrogenation of 3-quinuclidinone derivatives using
inexpensive hydrogen gas for the hydrogen source in the presence of an
asymmetric hydrogenation catalyst. As a result, the inventors of the
present invention found that the use of a readily available optically
active ruthenium metal complex having a diphosphine ligand and a
1,4-dimaine ligand for the asymmetric hydrogenation catalyst enabled
3-quinuclidinol derivatives of high optical purity to be produced at high
yield by direct asymmetric hydrogenation of 3-quinuclidinone derivatives
at high attainment rates for both enantiomeric excess (or enantiomeric
excess and diastereomeric excess) and catalyst efficiency, thereby
leading to completion of the present invention.

[0015]Thus, according to the present invention, a process for producing
optically an active 3-quinuclidinol derivative is provided as indicated
in (1) to (5) below.

(1) A process is provided for producing an optically active
3-quinuclidinol derivative represented by formula (III):

##STR00002##

(wherein, R represents a hydrogen atom, an unsubstituted or substituted C1
to C20 alkyl group, an unsubstituted or substituted C2 to C20 alkenyl
group, an unsubstituted or substituted C3 to C8 cycloalkyl group, an
unsubstituted or substituted C5 to C6 cycloalkenyl group, an
unsubstituted or substituted C7 to C18 aralkyl group or an unsubstituted
or substituted C6 to C18 aryl group, and * represents an optically active
carbon atom), comprising: asymmetrically hydrogenating a 3-quinuclidinone
derivative represented by formula (I):

##STR00003##

(wherein,

[0016]R is the same as previously defined) in the presence of a ruthenium
compound represented by formula (II):

Ru(X)(Y)(Px)n[R1R2C*(NR3R4)-A-R5R6C*(NR-
7R8)] (II)

(wherein,

[0017]X and Y respectively and independently represent a hydrogen atom, a
halogen atom, a carboxylate, a hydroxyl group or a C1 to C20 alkoxy
group;

[0018]Px represents a phosphine ligand;

[0019]n represents 1 or 2;

[0020]R1 to R8 respectively and independently represent a
hydrogen atom, an unsubstituted or substituted C1 to C20 alkyl group, an
unsubstituted or substituted C2 to C20 alkenyl group, an unsubstituted or
substituted C3 to C8 cycloalkyl group, an unsubstituted or substituted C5
to 06 cycloalkenyl group, an unsubstituted or substituted C7 to 018
aralkyl group or an unsubstituted or substituted C6 to C18 aryl group, or
either of R1 and R2 may bond with either of R3 and
R4, and either of R5 and R6 may bond with either of
R7 and R8, to form a ring;

[0021]* is the same as previously defined; and,

[0022]A represents an unsubstituted or substituted C1 to C3 alkylene group
that may have ether bond(s), an unsubstituted or substituted C3 to C8
cycloalkylene group, an unsubstituted or substituted arylene group or an
unsubstituted or substituted divalent heterocyclic group, and in the case
A is an unsubstituted or substituted C1 to C3 alkylene group, either of
R1 and R2 and either of R5 and R6 may bond to form a
ring).

[0023]R and * are the same as previously defined, and ** represents an
optically active carbon atom in the case R is other than a hydrogen
atom), comprising: asymmetrically dehydrogenating a 3-quinuclidinone
derivative represented by formula (I-1):

##STR00005##

(wherein, R is the same as previously defined) in the presence of a
ruthenium compound represented by the formula (II).(3) The process for
producing an optically active 3-quinuclidinol derivative described in (1)
or (2) above, wherein the ruthenium compound represented by formula (II)
is a ruthenium compound represented by formula (II-1):

Ru(X)(Y)(Px)n[R1C*H(NR3R4)-A-R1C*H(NR3R4)] (II-1)

(wherein, X, Y, Px, n, R1, R3, R4, * and A are the same as
previously defined).(4) The process for producing an optically active
3-quinuclidinol derivative described in (1) or (2) above, wherein the
ruthenium compound represented by formula (II) is a ruthenium compound
represented by formula (II-2):

Ru(X)(Y)(Px)n[R1C*H(NH2)-A-R1C*H(NH2)] (II-2)

(wherein, X, Y, Px, n, and * and A are the same as previously defined).(5)
The process for producing an optically active 3-quinuclidinol derivative
described in (1) or (2) above, wherein the ruthenium compound represented
by formula (II) is a ruthenium compound represented by formula (II-3):

Ru(X)2(Pxx)[R1C*H(NH2)-A-R1C*H(NH2)] (II-3)

(wherein, X, R1, * and A are the same as previously defined, and Pxx
represents an optically active phosphine ligand).

EFFECTS OF THE INVENTION

[0024]According to the present invention, an optically active
3-quinuclidinol derivative of high optical purity can be produced at high
attainment rates for enantiomeric excess or diastereomeric excess and
catalyst efficiency by using a readily available ruthenium compound as an
asymmetric reduction catalyst.

BEST MODE FOR CARRYING OUT THE INVENTION

[0025]The following provides a detailed explanation of the present
invention.

[0026]The present invention is a process for producing an optically active
3-quinuclidinol derivative represented by the formula (III) that
comprises asymmetric dehydrogenation of a 3-quinuclidinone derivative
represented by the formula (I) in the presence of a ruthenium compound
represented by the formula (II).

[0027]3-Quinuclidinone Derivative (I)

[0028]In the present invention, the 3-quinuclidinone derivative
represented by the formula (I) (to be referred to as the
"3-quinuclidinone derivative (I)") is used as a starting raw material.

[0029]In the formula (I), R represents a hydrogen atom, an unsubstituted
or substituted C1 to C20 alkyl group, an unsubstituted or substituted C2
to C20 alkenyl group, an unsubstituted or substituted C3 to C8 cycloalkyl
group, an unsubstituted or substituted C5 to C6 cycloalkenyl group, an
unsubstituted or substituted C7 to C18 aralkyl group or an unsubstituted
or substituted C6 to C18 aryl group.

[0032]Examples of C3 to C8 cycloalkyl groups include a cyclopropyl group,
cyclobutyl group, cyclopentyl group and cyclohexyl group.

[0033]Examples of C5 to C6 cycloalkenyl groups include a 1-cyclopentenyl
group, 2-cyclopentenyl group, 1-cyclohexenyl group, 2-cyclohexenyl group
and 3-cyclohexenyl group.

[0034]Examples of C7 to C18 aralkyl groups include a benzyl group,
α,α-dimethylbenzyl group, phenethyl group and benzhydryl
group.

[0035]Examples of C6 to C18 aryl groups include a phenyl group, 1-naphthyl
group, 2-naphthyl group and 3-anthracenyl group.

[0036]There are no particular limitations on the type or number of
substituents of the C1 to C20 alkyl groups and C2 to C20 alkenyl groups
provided they are within a chemically acceptable range. Examples of these
substituents include halogen atoms such as a fluorine atom, chlorine
atom, bromine atom or iodine atom; hydroxyl groups; C1 to 020 alkoxy
groups such as a methoxy group, ethoxy group, n-propoxy group, i-propoxy
group, n-butoxy group, s-butoxy group, i-butoxy group or t-butoxy group;
C7 to C18 aralkyloxy groups such as a benzyloxy group,
α,α-dimethylbenzyloxy group or phenethyloxy group; acylamino
groups such as an acetylamino group or benzoylamino group; sulfonylamino
groups such as a methanesulfonylamino group or toluenesulfonylamino
group; N-alkyl-N-acylamino groups such as an N-methyl-N-acetylamino
group, N-ethyl-N-acetylamino group, N-methyl-N-benzoylamino group or
N-ethyl-N-acylamino group; N-alkyl-N-alkylsulfonylamino groups such as
N-methyl-N-methylsulfonylamino group or N-ethyl-N-methylsulfonylamino
group; phthalimido groups; and oxygen-containing heterocyclic groups such
as a furanyl group, pyranyl group or dioxolanyl group.

[0037]There are no particular limitations on the type or number of
substituents of the C7 to C18 aralkyl groups, C6 to C18 aryl groups, C3
to C8 cycloalkyl groups and C5 to C6 cycloalkenyl groups provided they
are within a chemically acceptable range.

[0038]Examples of these substituents include halogen atoms such as a
fluorine atom, chlorine atom, bromine atom or iodine atom; hydroxyl
groups; C1 to C20 alkoxy groups such as a methoxy group, ethoxy group,
n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group,
i-butoxy group or t-butoxy group; C7 to C18 aralkyloxy groups such as a
benzyloxy group, α,α-dimethylbenzyloxy group or phenethyloxy
group; acylamino groups such as an acetylamino group or benzoylamino
group; sulfonylamino groups such as a methanesulfonylamino group or
toluenesulfonylamino group; N-alkyl-N-acylamino groups such as an
N-methyl-N-acetylamino group, N-ethyl-N-acetylamino group,
N-methyl-N-benzoylamino group or N-ethyl-N-acylamino group;
N-alkyl-N-alkylsulfonylamino groups such as
N-methyl-N-methylsulfonylamino group or N-ethyl-N-methylsulfonylamino
group; oxygen-containing heterocyclic groups such as a phthalimido group,
furanyl group, pyranyl group or dioxolanyl group; C1 to C20 alkyl groups
such as a methyl group, ethyl group, n-propyl group, i-propyl group,
n-butyl group, s-butyl group, t-butyl group, n-pentyl group or n-hexyl
group; C3 to C8 cycloalkyl groups such as a cyclopropyl group, cyclobutyl
group or cyclopentyl group; C2 to C20 alkenyl groups such as a vinyl
group, n-propenyl group, i-propenyl group, n-butenyl group, sec-butenyl
group, 1,3-butadienyl group, n-pentenyl group, 2-pentenyl group,
3-pentenyl group or hexenyl group; C5 to C6 cycloalkenyl groups such as a
1-cyclopentenyl group, 2-cyclopentenyl group, 1-cyclohexenyl group,
2-cyclohexenyl group or 3-cyclohexenyl group; C7 to C18 aralkyl groups
such as a benzyl group, α,α-dimethylbenzyl group or phenethyl
group; and C6 to C18 aryl groups such as a phenyl group, 1-naphthyl
group, 2-naphthyl group or 3-anthracenyl group.

[0039]There are no particular limitations on the 3-quinuclidinone
derivative represented by formula (I) with respect to the steric
configuration of carbon atoms substituted by R when R is not a hydrogen
atom, and may an optically active form or racemic mixture.

[0047]Px represents a phosphine ligand, there are no particular
limitations thereon provided it can be a ligand of the ruthenium compound
represented by the formula (II), and it is preferably an optically active
ligand.

[0048]Examples of the phosphine ligand include monodentate phosphine
ligands represented by the formula: PRARBRC, and bidentate
phosphine ligands represented by the formula:
RDREP-Q--PRFRG.

[0049]In the formulas PRARBRC and
RDREP-Q-PRFRG, RA to RG respectively and
independently represent an unsubstituted or substituted C1 to C20 alkyl
group such as a methyl group, ethyl group, n-propyl group, i-propyl
group, n-butyl group, s-butyl group, t-butyl group, n-pentyl group or
n-hexyl group; an unsubstituted or substituted C6 to C14 aryl group such
as a phenyl group, 1-naphthyl group or 2-naphthyl group; or an
unsubstituted or substituted C3 to C8 cycloalkyl group such as a
cyclopropyl group, cyclopentyl group or cyclohexyl group.

[0050]In addition, any two of RA, RB and RC may bond to
form an unsubstituted or substituted carbon ring, or RD and RE
or RF and RG may bond to form an unsubstituted or substituted
carbon ring.

[0051]Moreover, two of RA, RB and RC may bond to form an
unsubstituted or substituted heterocyclic group, and RD and RE
and/or RF and RG may bond to form an unsubstituted or
substituted C3 to C6 heterocyclic group such as a phosphotane group,
phosphotane group, phosphinane group or phosphepane group.

[0052]Q represents an unsubstituted or substituted C1 to C5 alkylene group
such as a methylene group, ethylene group, trimethylene group or
propylene group; an unsubstituted or substituted C3 to C8 cycloalkylene
group such as a xylenediyl group, cyclopropylene group, cyclobutylene
group, cyclopentylene group, cyclohexylene group or bicycloheptenediyl
group; an unsubstituted or substituted C6 to C22 arylene group such as a
phenylene group, naphthylene group, ferrocenylene group,
9,10-dihydroanthracenediyl group or xanthenediyl group (xanthene-4,5-diyl
group); an unsubstituted or substituted divalent group of an axially
symmetrical compound such as a 1,1'-biphenyl-2,2'-diyl group,
3,3'-bipyridyl-4,4-diyl group, 4,4-bipyridyl-3,3'-diyl group,
1,1'-binaphthyl-2,2'-diyl group or 1,1'-binaphthyl-7,7-diyl group; or a
divalent group of ferrocene.

[0053]There are no particular limitations on the type or number of the
substituents of each of the unsubstituted or substituted groups indicated
above provided they are within a chemically acceptable range. Specific
examples of these substituents include the same substituents as those
listed as examples of substituents of the aforementioned R, such as C7 to
C18 aralkyl groups.

[0054]Specific examples of monodentate phosphine ligands represented by
the formula: PRARBRC include tertiary phosphines in which
RA, RB and RC are all the same groups such as tri
ethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine,
tricyclohexylphosphine or tri(p-tolyl)phosphine; tertiary phosphines in
which two of RA, RB and RC are the same groups such as
diphenylmethylphosphine, dimethylphenylphosphine,
diisopropylmethylphosphine, 1-[2-(diphenylphosphino)ferrocenyl]ethyl
methyl ether or 2-(diphenylphosphino)-2'-methoxy-1,1'-binaphthyl; and
tertiary phosphines in which all of RA, RB and RC are
different such as cyclohexyl(O-anisyl)-methylphosphine,
ethylmethylbutylphosphine, ethylmethylphenylphosphine or
isopropylethylmethylphosphine.

[0062]In addition, BINAP derivatives, which have a substituent such as a
halogen atom, alkyl group, halogenated alkyl group, aryl group or alkoxy
group on the naphthyl ring and/or benzene ring of BINAP, are also
preferable examples of bidentate phosphine ligands.

[0063]Specific examples of the aforementioned BINAP derivatives include
bidentate phosphine ligands such as
[0064]2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl or
[0065]2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-1,1'-binaphthyl;
[0066]1-[2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine;
1-[2-(diphenylphosphino)ferrocenyl]ethyldiphenylphosphine;
[0067]1-[2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine;
bidentate phosphine ligands having a substituent such as a halogen atom,
alkyl group, halogenated alkyl group, aryl group or alkoxy group on a
benzene ring of the aforementioned ferrocene derivatives;
1-butoxycarbonyl-4-dicyclohexylphosphino-2-(diphenylphosphinomethyl)pyrro-
lidine; 1-butoxycarbonyl-4-diphenylphosphino-2-(diphenylphosphinomethyl)py-
rrolidine;

[0080]In addition, in bidentate phosphine ligands represented by the
formula: RDREP-Q-PRFRG, Q may bond with RD and
RF to form a bisheterocycle containing a phosphorous atom. Examples
of these bisheterocycles include bisphosphotane, bisphosphorane,
bisphosphinane and bisphosphepane.

[0081]Specific examples of bidentate phosphine ligands represented by the
formula: RDREP-Q-PRFRG, in which Q has bonded with
RD and RF to form a bisheterocycle containing a phosphorous
atom include 1,1'-di-t-butyl-[2,2']-diphosphoranyl (TANGPHOS),
2,2'-di-t-butyl-2,3,2',3'-tetrahydro-1H, 1'H-[1,1']-biisophosphindolyl
(DUANPHOS),
4,4'-di-t-butyl-4,4',5,5'-tetrahydro-3,3'-bi-3H-dinaphtho[2,1-c:1',
2'-e]phosphepine (BINAPINE), and 1,2-bis
{4,5-dihydro-3H-dinaphtho[1,2-c:2', 1'-e]phosphepino}benzene (BINAPHANE).

[0085]R1 to R8 respectively and independently represent a
hydrogen atom, an unsubstituted or substituted C1 to C20 alkyl group, an
unsubstituted or substituted C2 to C20 alkenyl group, an unsubstituted or
substituted C3 to C8 cycloalkyl group, an unsubstituted or substituted C5
to C6 cycloalkenyl group, an unsubstituted or substituted C7 to C18
aralkyl group or an unsubstituted or substituted C6 to C18 aryl group.

[0086]Specific examples of unsubstituted or substituted C1 to C20 alkyl
groups, unsubstituted or substituted C2 to C20 alkenyl groups,
unsubstituted or substituted C3 to C8 cycloalkyl groups, unsubstituted or
substituted C5 to C6 cycloalkenyl groups, unsubstituted or substituted C7
to C18 aralkyl groups and unsubstituted or substituted C6 to C18 aryl
groups of R1 to R8 include the same as those listed as examples
for the aforementioned R.

[0087]In addition, either of R1 and R2 may bond with either of
R3 and R4, and either of R5 and R6 may bond with
either of R7 and R8, to form a ring. Examples of cyclic
residues formed by either of R1 and R2 bonding with either of
R3 and R4 or either of R5 and R6 bonding with either
of R7 and R8 include a 2-pyrrolidinyl group, 2-indolyl group,
2-piperidinyl group, 1,2,3,4-tetrahydroisoquinolin-2-yl group and
1,2,3,4-tetrahydroxyisoquinolin-3-yl group.

[0088]Among these examples, R1 to R8 are all preferably hydrogen
atoms from the viewpoint of ease of synthesis and availability.

[0089]In addition, in the case A described below is an unsubstituted or
substituted C1 to C3 alkylene group, either of R1 and R2 may
bond with either of R5 and R6 to form a ring.

[0090]* indicates that the carbon atom is an optically active carbon atom.

[0091]A represents an unsubstituted or substituted C1 to C3 alkylene group
that may have an ether bond, an unsubstituted or substituted C3 to C8
cycloalkylene group, an unsubstituted or substituted C6 to C22 arylene
group or an unsubstituted or substituted divalent heterocyclic group.

[0092]Examples of C1 to C3 alkylene groups that may have an ether bond of
A include a methylene group, ethylene group, propylene group,
trimethylene group or --CH2--O--CH2-- group.

[0093]Examples of C3 to C8 cycloalkylene groups and C6 to C22 arylene
groups of A include the same groups as those listed as examples for the
aforementioned Q.

[0094]Examples of divalent heterocyclic groups of A include divalent
heterocyclic groups of 5-membered rings such as furan-3,4-diyl,
tetrahydrofuran-3,4-diyl, 1,3-dioxolan-4,5-diyl,
2-oxo-1,3-dioxolan-4,5-diyl, thiophen-3,4-diyl, pyrrol-3,4-diyl or
2-imidazolidinone-4,5-diyl; divalent heterocyclic groups of 6-membered
rings such as 1,4-dioxolan-2,3-diyl, pyrazin-2,3-diyl or
pyridazin-4,5-diyl; and, divalent condensed heterocyclic groups such as
1,4-benzoxolane-2,3-diyl.

[0095]There are no particular limitations on substituents in the
aforementioned C1 to C3 alkylene groups that may have an ether bond, C3
to C8 cycloalkylene groups, C6 to C22 arylene groups and divalent
heterocyclic groups provided they are chemically acceptable. Specific
examples of these substituents include the same substituents as those
listed as examples of substituents of C7 to C18 aralkyl groups of the
aforementioned R.

[0096]Furthermore, in the case A is an ethylene group having respective
substituents on different carbon atoms, two substituents of the ethylene
group may bond to form a hydrocarbon ring. Specific examples of A in such
cases include divalent hydrocarbon rings such as cyclopentan-1,2-diyl,
cyclohexan-1,2-diyl and 1,2-phenylene.

[0097]The ruthenium compound (II) used in the present invention is
preferably a ruthenium compound represented by the formula (II-1):

Ru(X)(Y)(Px)n[R1C*H(NR3R4)-A-R1C*H(NR3R4)] (II-1)

(wherein, X, Y, Px, n, R1, R3, R4, * and A are the same as
previously defined), more preferably a ruthenium compound represented by
the formula (II-2):

Ru(X)(Y)(Px)n[R1C*H(NH2)-A-R1C*H(NH2)] (II-2)

(wherein, X, Y, Px, n, R1, * and A are the same as previously
defined), and particularly preferably a ruthenium compound represented by
the formula (II-3):

Ru(X)2(Pxx)[R1C*H(NH2)-A-R1C*H(NH2)] (II-3)

(wherein, X, R1, * and A are the same as previously defined, and Pxx
represents an optically active phosphine ligand).

[0104]The production process of the present invention preferentially
produces any optically active 3-quinuclidinol derivative (III) by an
asymmetric hydrogenation reaction using the 3-quinuclidinone derivative
(I) as a starting raw material and the ruthenium compound (II) as a
hydrogenation catalyst.

[0105]The asymmetric hydrogenation reaction is carried out by
asymmetrically reducing the 3-quinuclidinone derivative (I) in the
presence of the ruthenium compound (II) and in the presence of hydrogen
gas at a prescribed pressure or a hydrogen donor by adding a base as
desired.

[0106]In addition, in the present invention, after forming the ruthenium
compound (II) by adding a ruthenium complex having a phosphine ligand and
a diamine compound which serve as production raw materials of the
ruthenium compound (II) to reaction system separately, and adding a base
as necessary, an asymmetric hydrogenation reaction can be carried out
within the reaction system by adding a substrate to the reaction system,
without removing the ruthenium compound (II).

[0107]Although varying according to the size of the reaction container and
catalyst activity, the amount of the ruthenium compound (II) used as a
catalyst is normally within the range of 1/5,000 to 1/200,000 times
moles, and preferably within the range of 1/10,000 to 1/100,000 times
moles, the reaction substrate in the form of the 3-quinuclidinone (I).

[0109]The amount of base added is 2 times moles or more and preferably
within the range of 2 to 50,000 times moles the ruthenium compound (II).

[0110]The asymmetric hydrogenation reaction can be carried out in a
suitable solvent. There are no particular limitations on the solvent used
provided it solubilizes the substrate and catalyst without impairing the
reaction. Specific examples of solvents include alcohols such as
methanol, ethanol, n-propanol, i-propanol, i-butanol or benzyl alcohol;
aromatic hydrocarbons such as benzene, toluene or xylene; aliphatic
hydrocarbons such as pentane or hexane; halogenated hydrocarbons such as
dichloromethane, chloroform, trichloromethane, carbon tetrachloride or
1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran (THF),
1,2-dimethoxyethane or 1,4-dioxane; amides such as N, N-dimethylformamide
(DMF), N,N-dimethylacetamide, 1,3-dimethylimidazolidine,
1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone or
hexamethylphosphoric triamide (HMPT); nitriles such as acetonitrile or
benzonitrile; and, DMSO.

[0111]One type of these solvents can be used alone or two or more types
can be used as a mixture. Among these, alcohols are used preferably since
the reaction products are alcohol compounds.

[0112]The amount of solvent used depends on the solubility of the
3-quinuclidinone derivative (I) and economic efficiency, and although the
reaction also proceeds in the absence of solvent or in a state near
highly diluted conditions depending on the case, the amount of solvent
used is normally within the range of 10 to 10,000 parts by weight, and
preferably within the range of 50 to 1,000 parts by weight, based on 100
parts by weight of the 3-quinuclidinone derivative (I).

[0113]The pressure of the hydrogen is normally 1×105 to
2×107 Pa, and is preferably within the range of
3×105 to 1×107 Pa from the viewpoint of
practicality.

[0114]A hydrogen storage alloy or diimide and the like can be used for the
hydrogen donor used. The amount used is normally within the range of 1 to
100 times equivalents the 3-quinuclidinone derivative (I).

[0115]The reaction temperature is normally within the range of -50 to
+200° C. and preferably within the range of 0 to 100° C.

[0116]In addition, although varying according to the reaction substrate
concentration and reaction conditions such as temperature and pressure,
the reaction temperature is normally from several minutes to several
days.

[0117]There are no particular limitations on the type of reaction, and the
reaction may be of a batch type or continuous type.

[0118]Following completion of the reaction, isolation and purification are
carried out using ordinary organic synthetic chemistry techniques to
enable the obtaining of the optically active 3-quinuclidinol derivative
(III).

[0119]Structures of target compounds can be identified and confirmed by
known analytical means such as elementary analysis, NMR, IR or mass
spectroscopy.

[0120]An optically active 3-quinuclidinol derivative obtained in the
manner described above is useful as a production raw material of active
ingredients of pharmaceuticals or production intermediates of those
active ingredients.

[0121]3-Quinuclidinol Derivative (III)

[0122]According to the present invention, an optically active
3-quinuclidinol derivative represented by the formula (III) (to be
referred to as the 3-quinuclidinol derivative (III)) can be obtained.

[0123]Namely, in the case of a compound represented by the formula (I),
any 3-quinuclidinol derivative (III) having an optically active carbon
atom indicated with an * can be obtained by asymmetric hydrogenation
reaction using the ruthenium compound (II) as a hydrogenation catalyst.
This is the result of any enantiomeric isomer being preferentially
obtained corresponding to an enantiomer of the ruthenium compound (II)
used.

[0124]In addition, in the present invention, the 3-quinuclidinol
derivative represented by the formula (III-1) can be obtained in the case
of using the 3-quinuclidinone derivative represented by the formula (I-1)
as a starting raw material.

[0125]In the case of a compound represented by the formula (I-1), if a
reaction is carried out by using as a starting raw material
3-quinuclidinone in which R in the formula is a hydrogen atom and using
the ruthenium compound (II) as a catalyst, either of the 3-quinuclidinols
(IIIa) and (IIIb) represented by the following formulas can be obtained.

##STR00008##

[0126]In addition, in the case of a compound represented by the formula
(I-1), if an asymmetric hydrogenation reaction is carried out using a
3-quinuclidinone derivative represented by formula (I-1) as a starting
raw material in which R in the formula is that other than a hydrogen atom
and using the ruthenium compound (II) as a hydrogenation catalyst, either
of the 3-quinuclidinol derivatives (IIIc) and (IIId) represented by the
following formulas can be obtained:

##STR00009##

(wherein, R is the same as previously defined).

[0127]An optically active 3-quinuclidinol derivative obtained by the
production process of the present invention is useful as a production raw
material of active ingredients of pharmaceuticals or production
intermediates of those active ingredients.

EXAMPLES

[0128]Although the following provides a more detailed explanation of the
present invention through examples thereof, the present invention is not
limited to only these examples.

[0129]Furthermore, the apparatuses used to measure physical properties in
each of the examples are as indicated below.

[0131]The ruthenium compound (II) used was synthesized in accordance with
the process described in Japanese Unexamined Patent Application, First
Publication No. 2002-284790.

Example 1

##STR00010##

[0133]1.63 g (13 mmol) of the 3-quinuclidinone (I) were added to a 50 ml
Schlenk tube and after reducing pressure inside the vessel with a vacuum
pump, argon was sealed inside. This procedure was repeated three times to
replace the inside of the vessel with argon 12.7 ml of 2-propanol and
0.26 ml (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide
(1.0M) were respectively added to the vessel with a glass syringe. After
completely dissolving the 3-quinuclidinone using an ultrasonic device,
the solution was frozen at the temperature of liquid nitrogen. After
reducing the pressure inside the vessel with a vacuum pump, the solution
was thawed using a heat gun. This freezing-degassing procedure was
repeated three times to obtain a substrate solution.

[0134]A polytetrafluoroethylene-coated stirrer bar and 1.4 mg of the
ruthenium compound (II) in the form of
(S)-1,1'-binapthyl-2,2'-bis(di-p-tolyl)phosphine ruthenium (II)
dichloride (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine complex
(1.3 μmol, S/C=(substrate: 13 mmol)/(ruthenium compound (II):1.3
μmol)=10,000) were added to a 100 ml stainless steel autoclave
(provided with a glass inner tube) followed by replacing the inside of
the vessel with argon. Next, the substrate solution was transferred to
the autoclave using a polytetrafluoroethylene tube.

[0135]The autoclave was connected to a hydrogen tank using a hydrogen feed
tube and hydrogen at 0.2 MPa was released 10 times to replace air inside
the feed tube with hydrogen. Subsequently, hydrogen at 1.0 MPa was sealed
in the autoclave vessel followed immediately by releasing hydrogen until
the pressure reached 0.2 MPa, and this procedure was repeated 10 times to
replace the inside of the vessel with hydrogen. Finally, hydrogen was
filled to a pressure of 2.0 MPa followed by stirring for 5 hours at 20 to
25° C.

[0136]Following completion of the reaction, 146.1 ml (1.105 mmol) of
distillation purified tetralin were added to the reaction solution as an
internal standard followed by stirring to achieve uniformity. When the
reaction mixture was analyzed by gas chromatography, 13 mmol of
(R)-3-quinuclidinol (3-R) were determined to have been formed at a
enantiomeric excess of 97% ee(R) (yield: 100%).

Example 2

[0137]The same reaction as Example 1 was carried out with the exception of
using (S)-1,1'-binaphthyl-2,2'-bis(diphenyl) phosphine ruthenium (II)
dichloride (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine complex
for the ruthenium compound (II) to obtain (R)-3-quinuclidinol (3-R). S/C,
conversion rate and enantiomeric excess are indicated below.

[0138]S/C: 10,000

[0139]Conversion rate: 100%

[0140]Enantiomeric excess: 97% ee(R)

Example 3

[0141]The same reaction as Example 1 was carried out with the exception of
using (S)-1,1'-binaphthyl-2,2'-bis(diphenyl) phosphine ruthenium (II)
dichloride (R,R)-hexane-2,5-diamine complex for the ruthenium compound
(II) to obtain (R)-3-quinuclidinol (3-R). S/C, conversion rate and
enantiomeric excess are indicated below.

[0142]S/C: 20,000

[0143]Conversion rate: 100%

[0144]Enantiomeric excess: 95% ee(R)

Example 4

[0145]1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol)
of {[(S)-(6,6'-dimethyl-1,1'-biphenyl-2,2'-diyl)-bis(diphenylphosphine)]r-
uthenium (II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31
μl (1.55 μmol) of a 0.05 M 2-propanol solution of
(2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an
autoclave in which the inside had been replaced with argon followed by
carrying out a degassing procedure and stirring for 30 minutes at room
temperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassium
tert-butoxide (1.0 M) were added thereto followed by stirring for 16
hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain
(R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excess
are indicated below.

[0146]S/C: 10,000

[0147]Conversion rate: 100%

[0148]Enantiomeric excess: 95% ee(R)

Example 5

[0149]1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol)
of {[(S)-(6,6'-dimethyl-1,1'-biphenyl-2,2'-diyl)-bis(di-p-tolylphosphine)-
]ruthenium (II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31
μl (1.55 μmol) of a 0.05 M 2-propanol solution of
(2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an
autoclave in which the inside had been replaced with argon followed by
carrying out a degassing procedure and stirring for 30 minutes at room
temperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassium
tert-butoxide (1.0 M) were added thereto followed by stirring for 16
hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain
(R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excess
are indicated below.

[0150]S/C: 10,000

[0151]Conversion rate: 100%

[0152]Enantiomeric excess: 96% ee(R)

##STR00011##

Example 6

[0153]The same reaction as Example 1 was carried out with the exception of
using (R)-1,1'-binaphthyl-2,2'-bis(diphenyl) phosphine ruthenium (II)
dichloride
(1S,2S,3S,4S)-2,3-O-isopropylidene-1,4-diphenylbutane-1,4-diamine complex
for the ruthenium compound (II) to obtain (S)-3-quinuclidinol (3-S). S/C,
conversion rate and enantiomeric excess are indicated below.

[0154]S/C: 5,000

[0155]Conversion rate: 100%

[0156]Enantiomeric excess: 95% ee(S)

Example 7

[0157]The same reaction as Example 1 was carried out with the exception of
using (R)-1,1'-binaphthyl-2,2'-bis(di-p-tolyl) phosphine ruthenium (II)
dichloride (S,S)-hexane-2,5-diamine complex for the ruthenium compound
(II) to obtain (S)-3-quinuclidinol (3-S). S/C, conversion rate and
enantiomeric excess are indicated below.

[0158]S/C: 10,000

[0159]Conversion rate: 100%

[0160]Enantiomeric excess: 97% ee(S)

Example 8

[0161]The same reaction as Example 1 was carried out with the exception of
using (R)-1,1'-binaphthyl-2,2'-bis(di-p-tolyl) phosphine ruthenium (II)
dichloride (S,S)-1,4-diphenylbutane-1,4-diamine complex for the ruthenium
compound (II) to obtain (S)-3-quinuclidinol (3-S). S/C, conversion rate
and enantiomeric excess are indicated below.

[0162]S/C: 10,000

[0163]Conversion rate: 100%

[0164]Enantiomeric excess: 98% ee(S)

Example 9

##STR00012##

[0166]397.7 mg (1.30 mmol) of a racemic mixture of
2-benzhydrylquinuclidin-3-one (1-2) and 1.2 mg (1.3 μmol) of
(S)-1,1'-binaphthyl-2,2'-bis(diphenyl)phosphine ruthenium (II) dichloride
(R,R)-hexane-2,5-diamine complex were placed in an autoclave in which the
inside had been replaced with argon. After adding 6.4 ml of 2-propanol
thereto and degassing, 0.13 mL (0.13 mmol) of a 2-propanol solution of
potassium tert-butoxide (1.0 M) were added thereto followed by stirring
for 18 hours at 20 to 25° C. at a hydrogen pressure of 1.0 MPa.
After concentrating the reaction solution, analysis of the crude
purification product by 1H-NMR indicated that only the syn form had been
formed. The reaction solution was then purified by silica gel column
chromatography (developing solvent: n-hexane:ethyl acetate=3:1 (volume
ratio)) to obtain 382 mg (1.30 mmol, yield: 96%) of
(2S,3S)-2-benzhydrylquinuclidin-3-ol (3-2). The optical purity of this
substance as measured by high-performance liquid chromatography (eluent:
acetonitrile:0.02 M aqueous disodium hydrogen phosphate=6:4 (volume
ratio), column: CHIRALCEL OD-RH, Daicel Chemical Industries, Ltd.) was
96% ee.

Example 10

[0167]The same reaction as Example 9 was carried out with the exception of
using (S)-1,1'-binaphthyl-2,2''-bis(diphenyl) phosphine ruthenium (II)
dichloride (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine complex
for the ruthenium compound (II) to obtain
(2S,3S)-2-benzhydrylquinuclidin-3-ol (3-2) at a yield of 99% and optical
purity of >99% ee.

Example 11

[0168]The same reaction as Example 9 was carried out with the exception of
using the compound represented by the following formula (12) for the
ruthenium compound (II) to obtain (2S,3S)-2-benzhydrylquinuclidin-3-ol
(3-2) at a yield of 96% and optical purity of >99.6% ee.

##STR00013##

Example 12

[0169]398.0 mg (1.30 mmol) of a racemic mixture of
2-benzhydrylquinuclidin-3-one (1-2), 1.1 mg (1.3 μmol) of
{[(S)-(6,6T-dimethyl-1,1'-biphenyl-2,2'-diyl)-bis(diphenylphosphine)]ruth-
enium (II) dichloride (DMF)n} complex, 6.4 ml of 2-propanol and 31 μl
(1.55 μmol) of a 0.05 M 2-propanol solution of
(2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an
autoclave in which the inside had been replaced with argon followed by
degassing and stirring for 30 minutes at room temperature. 0.13 mL (0.13
mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were
added thereto followed by stirring for 18 hours at 20 to 25° C. at
a hydrogen pressure of 1 MPa. The same post-treatment procedure as
Example 7 was carried out to obtain (2S,3S)-2-benzhydrylquinuclidin-3-ol
(3-2) at a yield of 97% and optical purity of >99% ee.

INDUSTRIAL APPLICABILITY

[0170]According to the present invention, an optically active
3-quinuclidinol derivative of high optical purity can be produced at high
attainment rates for enantiomeric excess or diastereomeric excess and
catalyst efficiency by using a readily available ruthenium compound as an
asymmetric reduction catalyst, thereby making the present invention
extremely industrially useful.